Numerous linkage and association studies have implicated chromosome 22q in the etiology of schizophrenia (Vallada et al., Psychiatr. Genet. 5:127-30 (1995); Gill et al., Am. J. Med. Genet. 16:40-5 (1996); Myles-Worsley et al., Am. J. Med. Genet. 88:544-50 (1999); Jorgensen et al., Am. J. Med. Genet. 114:245-52 (2002); DeLisi et al., Am. J. Psychiatry 159:803-12 (2002); Lewis et al., Am. J. Hum. Genet. 73:34-48 (2003); Takahashi et al., Am. J. Med. Genet. 120B:11-7 (2003)). Nonetheless, the precise location of the genes involved has yet to be resolved.
Possibly owing to genetic heterogeneity, analyses of positional candidates on this chromosome have resulted in conflicting results. The 22q11 region has received much attention, as its deletion in velo-cardio-facial syndrome correlates with increased propensity to develop schizophrenia (Ivanov et al., Br J Psychiatry. 183:409-13 (2003); van Amelsvoort et al., Genetic Curr. Psychiatry. Rep. 6:176-82 (2004); Williams and Owen, Curr Psychiatry Rep. 6(3): 176-82 (2004)). Candidates identified in this region include the catechol-O-methyltransferase (COMT) gene, an attractive candidate whose role has recently been challenged, and proline dehydrogenase, a gene whose role may be limited to Chinese lineages (Shifman et al., Am. J. Hum. Genet. 71:1296-302 (2002); Williams and Owen, (2004), supra; McGuffin et al., Curr. Psychiatry. Rep. 5:121-7 (2003); Williams et al., Am. J. Med. Genet. 120B:42-6 (2003); Handoko et al., Mol Psychiatry. 10:589-597 (2005) [Epub ahead of print Oct. 26, 2004]; Shirts and Nimgaonkar, Curr. Psychiatry. Rep. 6:303-12 (2004)). Other studies suggest a more distal location for a susceptibility gene in 22q12 or 22q13 (DeLisi et al., 2002, supra; Takahashi et al., Am. J. Med. Genet. 120B:11-7 (2003) et al., 2003). Here again, however, family-based transmission studies and evaluation of specific candidate genes have provided somewhat modest or, at times, contradictory, results (Vallada et al., Psychiatr. Genet. 5:127-30 (1995); Stober et al., Am. J. Med. Genet. 96:392-7 (2000); Meyer et al., Mol. Psychiatry 6:302-6 (2001); Takahashi et al., Am. J. Med. Genet. 120B:11-7 (2003); Georgieva et al., Psychiatr. Genet. 13:103-6 (2003); Kaganovich et al., Am. J. Med. Genet. 125B:31-7 (2004)).
Due to the severity of the disorder, the negative impact of a psychotic episode on a patient, and the diminishing recovery after each psychotic episode, there is a need to more conclusively identify individuals who have or are at risk of developing schizophrenia (SZ), schizotypal personality disorder (SPD) or schizoaffective disorder (SD), for example, to confirm clinical diagnoses, to allow for prophylactic therapies, to determine appropriate therapies based on their genotypic subtype, and to provide genetic counseling for prospective parents with a history of the disorder.